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    COVID-19 disease in children and adolescents following allogeneic hematopoietic stem cell transplantation: A report from the Turkish pediatric bone marrow transplantation study group
    (Wiley, 2024) Bozkurt, Ceyhun; Hazar, Volkan; Malbora, Baris; Kupesiz, Alphan; Aygunes, Utku; Fisgin, Tunc; Karakukcu, Musa
    BackgroundData on the risk factors and outcomes for pediatric patients with SARS-CoV-2 infection (COVID-19) following hematopoietic stem cell transplantation (HSCT) are limited.ObjectivesThe study aimed to analyze the clinical signs, risk factors, and outcomes for ICU admission and mortality in a large pediatric cohort who underwent allogeneic HSCT prior to COVID-19 infection.MethodIn this nationwide study, we retrospectively reviewed the data of 184 pediatric HSCT recipients who had COVID-19 between March 2020 and August 2022.ResultsThe median time from HSCT to COVID-19 infection was 209.0 days (IQR, 111.7-340.8; range, 0-3845 days). The most common clinical manifestation was fever (58.7%). While most patients (78.8%) had asymptomatic/mild disease, the disease severity was moderate in 9.2% and severe and critical in 4.4% and 7.6%, respectively. The overall mortality was 10.9% (n: 20). Deaths were attributable to COVID-19 in nine (4.9%) patients. Multivariate analysis revealed that lower respiratory tract disease (LRTD) (OR, 23.20, p: .001) and lymphopenia at diagnosis (OR, 5.21, p: .006) were risk factors for ICU admission and that HSCT from a mismatched donor (OR, 54.04, p: .028), multisystem inflammatory syndrome in children (MIS-C) (OR, 31.07, p: .003), and LRTD (OR, 10.11, p: .035) were associated with a higher risk for COVID-19-related mortality.ConclusionWhile COVID-19 is mostly asymptomatic or mild in pediatric transplant recipients, it can cause ICU admission in those with LRTD or lymphopenia at diagnosis and may be more fatal in those who are transplanted from a mismatched donor and those who develop MIS-C or LRTD. COVID-19 in children following HSCT is frequently asymptomatic/mild. Nonetheless, 12% of patients have such severe disease that they need intensive care. Adverse outcomes are expected in mismatched HSCT, lymphopenia, LRTD, and MIS-C.image
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    Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency
    (2020) Ghosh, Sujal; Bal, Sevgi Köstel; Edwards, Emily S J; Pillay, Bethany; Jimenez-Heredia, Raúl; Rao, Geetha; Erol Çipe, Funda; Salzer, Elisabeth; Zoghi, Samaneh; Abolhassani, Hassan; Momen, Tooba; Gostick, Emma; Price, David A; Zhang, Yu; Oler, Andrew J; Gonzaga-Jauregui, Claudia; Erman, Baran; Metin, Ayşe; İlhan, İnci; Haskoloğlu, Şule; İslamoğlu, Candan; Baskın, Kübra; Ceylaner, Serdar; Yılmaz, Ebru; Ünal, Ekrem; Karakukcu, Musa; Berghuis, Dagmar; Cole, Theresa; Gupta, Aditya Kumar; Hauck, Fabian; Hoepelman, Andy; Barış, Safa; Karakoç Aydıner, Elif; Özen, Ahmet; Kager, Leo; Holzinger, Dirk; Paulussen, Michael; Krüger, Renate; Meisel, Roland; Oommen, Prasad Thomas; Morris, Emma C; Neven, Benedicte; Worth, Austen J J; Montfrans, Joris M van; Fraaij, Pieter; Choo, Sharon; Doğu, Figen; Davies, E Graham; Burns, Siobhan; Dueckers, Gregor; Becker, Ruy Perez; Bernuth, Horst von; Latour, Sylvain; Faraci, Maura; Gattorno, Marco; Su, Helen; Pan-Hammarström, Qiang; Hammarström, Lennart; Lenardo, Michael J; Ma, Cindy S; Niehues, Tim; Aghamohammadi, Asghar; Rezaei, Nima; Ikinciogullari, Aydan; Tangye, Stuart G; Lankester, Arjan C; Boztuğ, Kaan
    Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity characterized predominantly by EBV-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and malignancy. A comprehensive understanding of the natural history, immune characteristics and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected clinical information of 49 patients from 29 families (CD27 n=33, CD70 n=16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority (90%) of patients were EBV+ at diagnosis, but only ~30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one (43%) patients developed autoinflammatory features including uveitis, arthritis and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.
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    ILC3 deficiency and generalized ILC abnormalities in DOCK8-deficient patients
    (Wiley, 2020) Eken, Ahmet; Cansever, Murat; Okuş, Fatma Zehra; Erdem, Şerife; Nain, Ercan; Azizoğlu, Zehra Büşra; Haliloğlu, Yeşim; Karakukcu, Musa; Özcan, Alper; Devecioğlu, Ömer; Aksu, Güzide; Arıkan Ayyıldız, Zeynep; Topal, Erdem; Karakoç Aydıner, Elif; Kıykım, Ayça; Metin, Ayşe; Erol Çipe, Funda; Kaya, Ayşenur; Artaç, Hasibe; Reisli, İsmail; Güner, Şükrü N.; Uygun, Vedat; Tezcan Karasu, Gülsün; Dönmez Altuntaş, Hamiyet; Canatan, Halit; Oukka, Mohamed; Özen, Ahmet; Chatila, Talal A.; Keleş, Sevgi; Barış, Safa; Ünal, Ekrem; Patıroğlu, Türkan
    BackgroundDedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper-IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8-deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans. MethodsPeripheral blood ILC1-3 subsets of 16 DOCK8-deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post-transplant DOCK8-deficient patients (n = 12) by flow cytometry and real-time qPCR. Sorted total ILCs from DOCK8- or STAT3-mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL-7, IL-23, and IL-12 by cell culture, flow cytometry, and phospho-flow assays. ResultsDOCK8-deficient but not STAT3-mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8-deficient ILC1-3 subsets had defective proliferation, expressed lower levels of IL-7R, responded less to IL-7, IL-12, or IL-23 cytokines, and were more prone to apoptosis compared with those of healthy controls. ConclusionDOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8-deficient patients to infections.